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CPR Exam 2 > 5. Erythrocyte and Heme Biochem > Flashcards

5. Erythrocyte and Heme Biochem Flashcards

1
Q

what is the average lifespan of RBCs

A

120 days

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2
Q

what is the structure of fetal Hb

A

Hb F = alpha2-gamma2

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3
Q

what are the components of adult Hb & which presents in higher quantity

A

Hb A = alpha2-beta2 = 97%

or alpha2-delta2

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4
Q

why does gamma levels drop and beta levels rise after birth

A

switching from Hb F to Hb A

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5
Q

what is the function of heme

and how is it incorporated in Hb

A

has Fe2+ & help carry O2

hydrophobic compound - 1 per subunit

total 4 hemes in Hb

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6
Q

what happens to confirmation of heme as O2 binds

A

usually Fe2+ slightly outside of plane

once O2 binds - Fe2+ moves into plane –> pulls down proximal histidine of Hb and changes interaction w/ associated globin chains

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7
Q

what it the difference btn the O2 dissociation curves of myglobin vs hemoglobin

A

myoglobin = hyperbolic

hemoglobin = sigmoidal - bc of cooperativity - as one O2 binds, makes O2 binding easier in other globin subunits

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8
Q

what is positive cooperativity

A

Hb binds O2 in cooperative manner

-one heme subunit binds O2 and facilitates binding of O2 in other heme subunit b/c confirmaiton change

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9
Q

At which stage of RBC development is the majority of Hb developed?

A

before extrusion of nucleus from normoblast

small amount is made in reticulocyte

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10
Q

How does a decreased pH and/or high 2,3-BPG affect affinity of O2 for Hb?

what is the purpose of this

A

decreases affinity

favor the release of O2 at level of tissues

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11
Q

what is the modulation that occurs with exercise

A

PO2 drops from 40 to 20 torr in exercising tissues

-favoring release of O2 to tissues

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12
Q

Why does fetal hemoglobin have a higher affinity for O2 than adult hemoglobin?

A

HbF = 2 alpha and 2 gamma chains

–> binds poorly to 2,3-BPG, –> increasing affinity for O2

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13
Q

what is the mutation that occurs in sickle cell anemia

& what is the consequence

A

glutamic acid –> valine at AA #6 in beta-globin

case polymerization, sickle shape RBCs - impede circulation

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14
Q

What is the current treatment for sickle cell anemia?

A

hydroxyurea to induce HbF

BUT its also an antineoplastic agent -toxic chemotherapeutic agent

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15
Q

where is iron most located in humans & where is it stored

A

Hb = 67% (vs, myoglobin- 5% and proteins- 1%)

stored = 27% - in intestines, liver, spleen & bone marrow

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16
Q

What does iron play a role in?

A

O2 transport in Hb and myoglobin

& ETC as a component of cytochromes

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17
Q

how is iron regulated

A

modulation of absorption

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18
Q

what happens to Fe2+ (animal product) after ingestion

A

enter enterocyte –> oxidize to Fe3+ by Ferrosxidase

–> store in ferritin –> can degrade and store in hemosiderin

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19
Q

what happens to non heme iron (Fe3+) from plant products after its ingested

A

convert to Fe2+ by ferric reductase (Dcytb) w/ the help of Vit C

  • now its easily abs and enters enterocyte via divalent transporter-1 (DMT1)
  • converted to Fe3+ by ferroxidase for storage OR export out of enterocyte by ferroportin
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20
Q

what is ferroportin

A

helps export Fe2+ out of enterocyte

needs Hephaestin for fxn

regulated by Hepcidin

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21
Q

what happesn once Fe2+ is in the blood

A

its converted to Fe3+ by ferroxidase

Fe3+ then binds transferrin for transport to target tissues

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22
Q

how does the uptake of transferrin happen?

A

receptor mediated endocytosis via transferrin receptor (TfR)

  • internalized via clathrin into endosome
  • low pH of endosome - release transferrin from receptor
  • uptake iron in mito via DMT1
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23
Q

how is iron homeostasis regulated

A

modulate abs by Hepcidin (made in liver)

bind to ferroportin when high Fe levels - internalize ferroportin and degrades in lysosome –> decrase iron abs

aka kills the transporter

*hepcidin is regulated by protein transferrin, its receptor and human homeostatic iron regulator protein (HFE)

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24
Q

what are causes of iron deficiency

and what does it lead to

A

insufficient dietary iron/abs, excess blood loss, overuse of asprin, ulcer of GI tract

causes hypochromic microcytic anemia

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25
what is hereditary hemochromatosis (HH) how does it happen, what does it lead to and how do you treat it
increased abs of iron --\> accumulate in heart, liver and pancreas ==\> lead to liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis & heart failure = auto recessive - mutation in hereditary hemochromatosis gene - iron overlad = 15 g in body (instead of 3) treat w/ blood letting nad iron chelators
26
what do you get if you have a deficiency of folate & vit B12
megaloblastic anemia --\> large RBCs - MCV \> 100 fL but normal Hb content in relation to size -occurs bc diminished synthesis of DNA in RBC development
27
how does megaloblastic macrocytic anemic look in bone marrow vs RBCs
bone marrow: large RBCs & hypersegmented neutrophils RBCs- increased vol & macrocytic, normochromic cells in blood smear
28
what reduces folate & what does it make
dihydrofolate reductace 1st add 2 H+ - DHF and then add 2 more = **THF**= active from
29
why is THF important
**synthesis of purines and pyrimidine thymine** **-vital role in DNA synthesis** -1 C transfer - gene regulation and synthetic path for choline, serine, glycine and methionine
30
how is folic acid abs-ed
abs in SI (jejunum) most dietary = DHF so after abs reduce to _N5-methyl-THF - primary circulating form_ liver stores 5-10 mg folate (last up 3-6 months)
31
what is methotrexate and how does it work
antineoplastic agent inhibitor of DNA synthesis (inhibit dihydrofolate reductase --\> dont reduce DHF to THF ==\> so no DNA & purine synthesis)
32
what happens if you dont have Vit B12
folate trap folate stuck as N5-methyl-THF so cant remove methyl group to get THF --\> mess with purine, pyr & DNA synthesis
33
how does most of B12 deficiency occur
lack of intrinsic factor - supposed to carry B12 to ileum from where its released to blood stream - w/o it you have trouble abs-ing B12
34
How is dietary B12 absorbed?
1. - R-binder proteins bind B12 in stomach 2. - Intrinsic factor made by parietal cells 3. - pancreas produces proteases to release B12 from R-binder proteins 4. - Intrinsic factor carries B12 do ileum where it is absorbed 5. - IF-B12 complex is carried by transcobalamin II 6. IF-B12 complex taken up by cells via receptor mediated endocytosis
35
what is pernicious anemia
Vit B12 deficiency bc lack of intrinsic factor a type of megaloblastic macrocytic anemia
36
What is considered a low serum folate?
\<3 ng/mL
37
What is considered a low serum B12?
\<350 pg/mL
38
What is the Schilling test?
a test that measures vitamin B12 absorption with and without intrinsic factor; if radioactive B12 present when administering CO-labeled B12 w/ IF then pos for pernicious anemia test for pernicious anemia
39
what is the structure of heme
heterocyclic perphyrin ring w/ iron present in center four 5-membered rings w/ N connected by single C -Fe2+
40
what are the 3 phases of heme biosynthesis & where do they occur
1. mitochondrial 2. cytosolic 3. mitochondial primarily in liver and erythroid cells of bone marrow
41
what are the steps of the 1st phase of heme synthesis
purpose = generate ALA
42
what are the steps of phase 2 of heme biosynthesis
purpose = generate coproporphyrinogen III (has porphyrin rings)
43
what is the 3rd phase of heme synthesis
purpose = generation of protoporphyrin & intoduction of iron to from heme
44
what does ALA synthase need to work
needs B6 -w/o B6- anemia bc heme synthesis doesnt occur
45
what happens in lead poisoning
**lead inactivates ALA dehydratase & Ferrochelatase** get accumulation of: 1. ALA - neurotoxic - lead to neurological symptoms 2. protoporphyrin IX cause anemia (microcytic & hypochromic) & impacts ATP synthesis & energy metabolism
46
what are porphyrias & how are they caused
inherited metabolic disorder -defects in heme systhesis types depend on where synthesis is inhibited
47
what is acute intermittent porphyria caused by & what are its consequences
defective PBG deaminase in liver = auto dom -excess production of ALA & PBG periodic attach of abdominal pain & neurolocial dysfxn type = hepatic porphyria
48
what is congenital erythropoietic porphyria & what are is its consequences
defective **uropophyrinogen III synthase** (in RBCs) = auto rec -accumulate _uroporphyrinogen I and its red colored, oxidation product uroporphrin I_ ==\> photosensitivity, red urine and teeth, hemolytic anemia type = erythropoietic porphyria
49
what is the cause for porphyria cutanea tarda & what are its consequences
defective uroporphyrinogen decarboxylase - auto dom - accumulate uroporphyinogen III --\> converts to urophorphyinogen I and uroporphyrin oxidation products ==\> photosensitivity, results in vesicles and bullae on skin, wine red urine type = hematoerythropoietic
50
what is the cause of variegate porphryia & what does it lead to
defective protoporphyrinogen IX oxidase -auto dom (aka celebrity porphyrias) ==\> photosensitivity and neurologic symptoms and development delay in children, intermittent episodes of abd pain, delirum, hallucinations/convulsions type = hepatic porphyria
51
what is the reticulo-endothelial system
system that degrades Hb into globin and heme globin broken down to AA and heme is processed fro degradation
52
what is heme oxygenase and what is the result of its rxn
enzyme that removes bridge btn pyrrole rings of heme (require O2) relase CO, oxidize iron to ferric form, make biliverdin
53
what converts biliverdin to bilirubin
biliverdin reductase
54
What is free bilirubin bound to and where is it transported to?
albumin -\> transported to liver where it is conjugated
55
What is the rate limiting enzyme in bilirubin conjugation?
UDP glucuronyl transferase rxn = BR-monoglucuronide --\> BR-diglucuronide f
56
What is the fate of conjugated bilirubin (bilirubin-diglucuronide)?
empty into the gall bladder
57
What are the products of BR-diglucuronide when released from the gall bladder into the small intestine? \*(released in response to food)
1. reduction to _urobilinogen_ 2. some urobilinogen is reabsorbed by kidneys to make _urobilin_ (yellow pigment in urine) 3. _stercobilin_ (red-brown pigment in feces)
58
What are normal levels of unconjugated and conjugated bilirubin?
unconjugated: 0.2-0.9 mg/dL conjugated: 0.1-0.3 mg/dL
59
What is the cause of pre-hepatic jaundice?
Increased unconjugated bilirubin production (hemolytic anemias may cause this) ex: excess hemolysis, internal hemorrhage, incompatibility of maternal-fetal blood group, uptake capacity of liver uptake
60
What are the clinical findings in pre-hepatic jaundice?
elevated unconjugated levels of BR normal ALT and AST (bc everything beyond the liver is fine) urobilinogen in urine
61
What is the cause of intra-hepatic jaundice?
* impaired hepatic uptake, conjugation, or secretion of conjugated BR * Can be caused by cirrhosis, hepatitis, _Criggler-Najjar syndrome, and Gilbert syndrome_
62
What are the clinical findings of intra-hepatic jaundice?
increase in ALT and AST variable increase in unconjugated/conjugated BR normal urobilinogen levels in urine
63
What are the causes of post-hepatic jaundice?
Defect with bilirubin excretion/decreased bile flow caused by obstruction to biliary drainage, cholangiocarcinoma, gallstones, lesions, drugs
64
What are the clinical findings in post-hepatic jaundice?
1. elevated blood levels of conjugated BR 2. Normal AST and ALT 3. Conjugated BR in urine (dark) 4. No urobilinogen in urine 5. No stercobilin in feces (pale stool)
65
What is the cause of neonatal jaundice?
Immature hepatic metabolic pathways deficiency of UDP-GT enzyme breakdown of fetal Hb as it is replaced with adult Hb --\> accumulate excess BR
66
What is the treatment for neonatal jaundice?
1. phototherapy (blue fluorescent light causes BR to convert to more soluble isomer) 2. IM injection of tin-mesoporphyrin (inhibits heme oxygenase)
67
What is the cause of Type 1 Criggler-Najjar syndrome?
UDP-GT deficiency: complete absence of gene =severe hyperbilirubinemia BR accumulates in brain --\> cause kernicturus (encephalopathy)
68
What is the treatment of Type 1 Criggler-Najjar syndrome?
blood transfusions phototherapy heme oxygenase inhibitor oral CaPO4 and carbonate liver transplant
69
What are the two benign UDP-GT disorders?
Type II Criggler-Najjar syndrome and Gilbert syndrome
70
What is the color progression of a bruise and their associated hemoglobin byproduct?
- Red = heme - green = biliverdin - orange = bilirubin - reddish brown = hemosiderin

CPR Exam 2 (20 decks)

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